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Introduction
Major depressive disorder (MDD) has a heterogeneous aetiology and the contribution of environmental factors is at least equivalent to that of genetic factors. A genetic diathesis predisposes individuals to the disorder in the context of life stressors (Kendler et al. 2001). Environmental factors are now taken into account in studies of MDD, which is not a trivial task because their evaluation is usually retrospective. Moreover, it is not explicit which stressful events are the most relevant, ranging from acute to chronic or traumatic stress events. The evidence suggests that the acute and recent stress is more relevant, compared with chronic and distal events (for a review see Monroe & Reid, 2008).
In the following sections we consider some of the possible factors that play a role in the gene-environment interaction relevant to the concept of vulnerability to MDD.
The serotonergic system
Serotonergic vulnerability (Jans et al. 2006) is an increased sensitivity to natural or experimental alterations of the serotonergic system, such as genetic factors, female gender, personality characteristics (neuroticism), environmental stress (prenatal stress, life experiences) or drug use. An insertion/deletion polymorphism in the serotonin transporter-linked promoter region 5-HTTLPR modulates serotonin transporter gene (SLC6A4) expression, where the short allele (S) is associated with lower expression levels compared to the long allele (L). Importantly, the risk for depression has been associated with an interaction of the S allele with stressful life events (Caspi et al. 2003). What are the neural mechanisms of such an interaction? Neuroimaging studies show that, in response to aversive visual signals, S allele carriers demonstrate amygdala hyperactivity and also altered connectivity between the pregenual anterior cingulate cortex (ACC) and the amygdala (for a meta-analysis see Munafo et al. 2008). In other words, people who genetically have low activity of 5-HTTLPR, and consequently are at risk for developing depression, demonstrate an overactivity of the amygdala to aversive signals. These experiments are regarded as modelling the brain's responsivity to potentially stressful environmental signals. A functional magnetic resonance imaging (fMRI) study (Canli et al. 2006) has indeed found that the life stress measure correlated positively with resting activation in the amygdala and hippocampus in S allele carriers and negatively in L allele carriers.
The literature indicating a net inhibitory...